1. Structural Data Analysis a. Impulsivity, Compulsivity, and Salience Network Volume in Alcohol Dependence. Convergent preclinical and clinical evidence has linked the anterior insula to impulsivity and alcohol-associated compulsivity. In this study, we investigated self-report impulsivity, decisional impulsivity, self-report compulsivity, and structural neuroimaging measures in a sample of alcohol dependent individuals. We found that alcohol dependent individuals had smaller anterior insula and anterior cingulate volumes, as well as thinner anterior insula cortices. Anterior insula and anterior cingulate structural measures were negatively associated with self-report impulsivity, decisional impulsivity, and compulsivity measures. Our results suggest that addiction endophenotypes are associated with salience network morphometry in AUD (Grodin et al., 2017). b. Addiction ENIGMA. Jointly, with our counterparts at the National Institute on Drug Abuses Neuroimaging Research Branch of Dr. Elliot Stein, we initiated the NIH Addiction Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA). This initiative is part of the Addiction-ENIGMA consortium, a large, multi-site, data-pooling initiative focused on genetics and the brain that has analyzed tens of thousands of study participants at more than 100 labs in over 30 countries. We continued our collaboration with this big data consortium. As a result, two additional manuscripts were published. i. Hemispheric asymmetry of human brain. This study presented the largest-ever analysis of cerebral cortical asymmetry and its variability across individuals, which contained over 17,000 MRI images from nearly 100 data set. In addition to population-level asymmetries, this study also revealed some asymmetric variability due to age, sex, and genetic heritability (Kong et al., 2018). ii. We have recently completed our contribution to a study measuring the gray matter volume in brain of various addiction populations. One of the objectives in this study was to determine whether there are common regions affected by various substance use disorders (SUD). In this study Alcohol dependence showed the greatest effects, in particular, the insula and the medial orbitofrontal cortex. The results indicate the potential utility of these common brain pathology as well as the differential patterns of regional volumes as biomarkers (Mackey et al., 2018). 2. Cerebellar recovery of alcohol dependent patients during short term abstinence. We are continuing our work that started as a collaboration with Dr. George Fein of Neurobehavioral Research, Inc. (NRI) in a funded U01 grant to develop and apply a 30 parcel active appearance model of the cerebellum on prospective motion tracking and corrected structural MRIs. CNIRC plays a key role in identifying appropriate subjects from ongoing studies in order to maximize the clinical, behavioral, and neuropsychological data available for analysis. 3. Omnibus Alcohol Neuroimaging Assesments The purpose of this study is to obtain a standard set of assessments, including brain behavioral, structural, functional, and connectivity (structural and functional) information, on all NIAAA research participants to a) to determine how individual differences in brain structure and evoked responses relate to generalized trait personality and behavior differences (as assessed by psychometric questionnaire instruments and behavioral measures); and b) to determine whether these individual differences relate specifically to genetic polymorphisms in genes governing neurotransmitter activity. We have been analyzing some of this data in further understanding the pathology of alcohol addiction. This in turn might enable us to identify and establish an Addictions Neuroimaging Assessment (ANiA) (Voon et al. 2018, submitted to Journal of NeuroPsychoPharmacology). Create a standardized neuroimaging assessment to provide AD subtyping phenotypes using information from: o Resting state and task driven functional connectivity; o Neurocircuitries associated with AD domains; o Gray and white matter structural integrity of the human brain in various stages of this heterogeneous disease. o Develop a big data system that enables the use of ANA and ANiA assessments and phenotypic data. o Determine the neural correlates (i.e. networks) associated with the domains and neuroclinical measures of alcohol use disorders. o Utilize innovative approaches such as machine learning to assist in individualized patient treatment, treatment efficacy, and relapse prediction. We have been analyzing some of this data in further understanding the pathology of alcohol addiction. a. Negative Affects in Anxious Patients with Alcohol Use Disorder. Studies have shown association between substance use disorders and mood and anxiety disorders. Compared to neutral faces, amygdala preferentially responds to fearful faces in contrast to neutral faces and habituates rapidly. Anxiety prone individuals have shown greater bilateral amygdala and insula activity to negative emotional faces. The amygdala response to emotional faces in patients with AUD has been somewhat contradictory. Some studies, including our own lab, have shown that anxious patients with AUD show a blunted response to emotional stimuli during fMRI in anterior cingulate cortex, amygdala, and hippocampus. While, others have characterized patients with AUD as having a greater tendency to experience negative emotion and impulsivity and a lack of social constraint. In this preliminary study we have examined the association between an alcohol use severity, anxiety score, and alterations in brain activation during exposure to negative facial emotion stimuli. Our initial results indicate a stronger association between STAI-T anxiety score and alcohol use severity as measured by AUDIT score in participants with both AUD and anxiety symptoms in comparison to control subjects and AUD participants without anxiety. The neuroimaging data suggests patients with AUD and anxiety symptoms show hypersensitivity to negative affects as demonstrated by response to angry facial expression stimuli. The hyperactivation of caudate might point to increased valuation of this type of emotions. On the other hand, the hypoactivation of anterior cingulate gyrus may suggest an inability of anxious AUD participants to normalize their response to fearful stimuli. The hyperactivity of AUD in left precuneus demonstrates the potential attention bias across AUD to negative affects. Further investigation is needed to include female participants as well as control subjects with anxiety diagnosis only to be able to generalize these preliminary findings. Our preliminary data also motivates future studies to investigate the relationship between anxiety and alcohol use and its effects on neuroimaging data. b. Threat processing and Association with Serotonin Transporter. DNA methylation of the serotonin transporter gene (SLC6A4) has implications in brain functions. In this study which is a collaboration with Dr. Lohoffs CGET the association between SLC6A4 promoter methylation and threat-related amygdala activation, measures of alcohol use, and depressive symptom severity is investigated. Results did not reveal an association between SLC6A4 promoter methylation and threat-related amygdala activation in HCs or individuals with AUD. However, one of the methylation sites (CpG #19 - located 84 base pairs upstream of the TSS), which was previously associated with threat-related amygdala reactivity in healthy individuals, was significantly increased in individuals with AUD compared to controls and significantly correlated with measures of alcohol use and depressive symptoms. More analysis of this data is underway.